Vertex Initiates Phase 3 Study of VX-659, Tezacaftor and Ivacaftor as a Triple Combination Regimen for People with Cystic Fibrosis Who Have Two Copies of the F508del Mutation

-Global Phase 3 study to enroll approximately 100 patients with the
most common genetic form of the disease-

-Phase 2 data showed mean absolute improvement in ppFEV1 of
9.7 percentage points when VX-659 was added in people with CF who have
two F508del mutations who were already receiving tezacaftor and
ivacaftor; triple combination regimen was generally well tolerated-

Vertex
Pharmaceuticals Incorporated (NASDAQ:VRTX) today announced that it
is initiating a Phase 3 study of VX-659, tezacaftor and ivacaftor as an
investigational triple combination regimen for people with cystic
fibrosis (CF) who have two copies of the F508del mutation, the
most common genetic form of the disease. The study will enroll
approximately 100 patients, and the primary endpoint of the study is the
mean absolute change from baseline in percent predicted forced
expiratory volume in one second (ppFEV1) at week four of
treatment. The study is designed to support the submission of an
application for approval in patients with two copies of the F508del
mutation in the U.S. using data from the 4-week primary efficacy
endpoint together with 24-week safety data generated from the recently
initiated Phase 3 study in patients with one F508del mutation and
one minimal function mutation.

The initiation of the Phase 3 study in people with CF who have two
copies of the F508del mutation is based on data announced today
from a Phase 2 study that showed a mean absolute improvement in ppFEV1
of 9.7 percentage points from baseline through week four of treatment
when VX-659 (400 mg) was added in people with CF who have two F508del mutations
and were already receiving tezacaftor in combination with ivacaftor. In
the Phase 2 study, the VX-659 triple combination regimen was generally
well tolerated, the majority of adverse events were mild to moderate in
severity and there were no discontinuations due to adverse events.

"We continue to make rapid and significant progress in our efforts to
advance our two triple combination regimens into Phase 3 development,
with an ultimate goal of bringing the best triple combination to
patients as quickly as possible," said Jeffrey Chodakewitz, M.D.,
Executive Vice President and Chief Medical Officer at Vertex. "The first
Phase 3 study we announced in February is designed to support approval
of the VX-659 triple combination in patients with one F508del
mutation and one minimal function mutation who currently have no
treatment that addresses the underlying cause of disease. This second
study is designed to enable us to broaden the potential label for this
regimen to include those with the most common genetic form of cystic
fibrosis."

About the Phase 3 Study

The randomized, double-blind, controlled Phase 3 study will evaluate
four weeks of treatment with VX-659 or placebo in combination with
tezacaftor and ivacaftor in approximately 100 patients ages 12 years or
older who have two F508del mutations. Approximately 50 patients
will receive VX-659, tezacaftor and ivacaftor and approximately 50 will
receive placebo, tezacaftor and ivacaftor. All patients will receive
tezacaftor in combination with ivacaftor during a 4-week run-in prior to
the start of the triple combination treatment period. The primary
endpoint of the study is the mean absolute change in lung function (ppFEV1)
from baseline (end of the 4-week tezacaftor/ivacaftor run-in) at week
four of treatment with VX-659 in combination with tezacaftor and
ivacaftor compared to those who received placebo, tezacaftor and
ivacaftor. Key secondary endpoints will also be measured at week four
and include changes in patient-reported outcomes as measured by the
respiratory domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R)
and change in sweat chloride.

The study will evaluate a fixed-dose combination of VX-659 (240 mg) with
tezacaftor (100 mg) and ivacaftor (150 mg) in the morning followed by
ivacaftor (150 mg) in the evening, which is the same dosing regimen
being evaluated in the ongoing Phase 3 study in patients with one F508del
mutation and one minimal function mutation. An open-label extension
study will be conducted where all eligible patients, including those who
received placebo, tezacaftor and ivacaftor, will receive the triple
combination regimen for up to an additional 96 weeks.

The study is designed to support an application for U.S. Food and Drug
Administration (FDA) approval of the VX-659 triple combination regimen
in patients with two copies of the F508del mutation based on data
from the 4-week primary efficacy analysis and secondary safety analysis
and on 24-week safety data from the Phase 3 study in patients with one F508del
mutation and one minimal function mutation. Vertex plans to use the
study in patients with two F508del mutations to broaden the
potential label for the VX-659 triple combination regimen and does not
anticipate that the study will impact its initial planned submission of
a New Drug Application to the U.S. FDA for patients with one F508del
mutation and one minimal function mutation. Data from the study in
patients with two F508del mutations will also be used to support
planned regulatory submissions in Europe and other regions.

The data announced today are from Part 2 of an ongoing randomized,
double-blind, controlled Phase 2 study where the primary objectives are
safety, tolerability and efficacy as assessed by mean absolute change in
ppFEV1 from baseline (end of the 4-week tezacaftor/ivacaftor
run-in period) through week four of treatment. Secondary endpoints
include absolute change in sweat chloride and change in the CFQ-R
respiratory domain score, among others.

All patients received a 4-week run-in of tezacaftor in combination with
ivacaftor. Patients were then randomized to add either VX-659 or placebo
to tezacaftor and ivacaftor for four weeks. After the 4-week triple
combination dosing period, all patients received four weeks of
tezacaftor and ivacaftor, followed by a 4-week safety follow-up period.
In the triple combination dosing period of the study, patients received
a morning dose of VX-659 (400 mg), or placebo, in addition to a
fixed-dose combination of tezacaftor (100 mg) and ivacaftor (150 mg) in
the morning followed by an evening dose of ivacaftor (150 mg) alone.

Safety Data: The triple combination regimen was generally well
tolerated. The majority of adverse events were mild or moderate. No
serious adverse events were reported in the triple combination group and
one serious adverse event (pulmonary exacerbation) was reported in the
group that received tezacaftor in combination with ivacaftor. There were
no discontinuations due to adverse events in either treatment group, and
there were no treatment interruptions. The most common adverse events
(>10%), regardless of treatment group, were cough, infective pulmonary
exacerbation, nasal congestion, nausea, sputum increased, vomiting,
headache, abdominal pain upper, blood creatine phosphokinase increased,
diarrhea, oropharyngeal pain, rash and upper respiratory tract infection.

Efficacy Data: This part of the study evaluated the addition of
VX-659, or placebo, to ongoing tezacaftor/ivacaftor treatment for a
4-week triple combination dosing period in 29 patients who have two F508del
mutations (11 in the placebo/tezacaftor/ivacaftor arm, 18 in VX-659
triple combination arm). A summary of the within-group lung function and
sweat chloride data is provided below:

* all p-values are within group p-values based on mixed effect
models; values expressed as ‘ThroughDay 29' are the
average of Day 15 and Day 29 measures

A secondary endpoint in the study measured mean absolute within-group
change in the respiratory domain of CFQ-R,1 a validated
patient-reported outcome measure, at Day 29. The mean absolute
improvement for patients who received the VX-659 triple combination was
19.5 points. The improvement for those who received placebo in addition
to tezacaftor and ivacaftor was 2.9 points.

About CF

CF is a rare, life-shortening genetic disease affecting approximately
75,000 people in North America, Europe and Australia.

CF is caused by a defective or missing cystic fibrosis transmembrane
conductance regulator (CFTR) protein resulting from mutations in the CFTR
gene. Children must inherit two defective CFTR genes — one from
each parent — to have CF. There are approximately 2,000 known mutations
in the CFTR gene. Some of these mutations, which can be
determined by a genetic test, or genotyping test, lead to CF by creating
non-working or too few CFTR proteins at the cell surface. The defective
function or absence of CFTR protein results in poor flow of salt and
water into and out of the cell in a number of organs. In the lungs, this
leads to the buildup of abnormally thick, sticky mucus that can cause
chronic lung infections and progressive lung damage in many patients
that eventually leads to death. The median age of death is in the
mid-to-late 20s.

About Vertex

Vertex is a global biotechnology company that invests in scientific
innovation to create transformative medicines for people with serious
and life-threatening diseases. In addition to clinical development
programs in CF, Vertex has more than a dozen ongoing research programs
focused on the underlying mechanisms of other serious diseases.

Founded in 1989 in Cambridge, Mass., Vertex's headquarters is now
located in Boston's Innovation District. Today, the company has research
and development sites and commercial offices in the United States,
Europe, Canada and Australia. Vertex is consistently recognized as one
of the industry's top places to work, including being named to Science
magazine's Top Employers in the life sciences ranking for eight years in
a row. For additional information and the latest updates from the
company, please visit www.vrtx.com.

Vertex initiated its CF research program in 2000 as part of a
collaboration with CFFT, the nonprofit drug discovery and development
affiliate of the Cystic Fibrosis Foundation. KALYDECO®
(ivacaftor), ORKAMBI® (lumacaftor/ivacaftor), SYMDEKO™
(tezacaftor/ivacaftor and ivacaftor), VX-440, VX-152, VX-659 and VX-445
were discovered by Vertex as part of this collaboration.

Special Note Regarding Forward-looking Statements

This press release contains forward-looking statements as defined in the
Private Securities Litigation Reform Act of 1995, including, without
limitation, Dr. Chodakewitz's statements in the third paragraph and the
information provided regarding (i) the timing and design of Vertex's
Phase 3 study for VX-659, (ii) the potential to use the study to support
regulatory applications, (iii) the relationship between the study in
patients with two copies of the F508del mutation and the study
that the company is conducting in patients with one F508del
mutation and one minimal function mutation and (iv) Vertex's plans to
initiate multiple additional Phase 3 studies of VX-659 and VX-445 triple
combination regimens in 2018. While Vertex believes the forward-looking
statements contained in this press release are accurate, these
forward-looking statements represent the company's beliefs only as of
the date of this press release, and there are a number of factors that
could cause actual events or results to differ materially from those
indicated by such forward-looking statements. Those risks and
uncertainties include: (i) that Vertex could experience unforeseen
delays in initiating its Phase 3 studies to evaluate VX-659 and/or
VX-445, (ii) that data from the Phase 3 development programs may not
support approval of the company's triple combination regimens due to
safety, efficacy or other reasons, and (iii) other risks listed under
Risk Factors in Vertex's annual report and quarterly reports filed with
the Securities and Exchange Commission and available through the
company's website at www.vrtx.com.
Vertex disclaims any obligation to update the information contained in
this press release as new information becomes available.

(VRTX-GEN)

1 CFQ-R results reported are based on a mixed effect model
not adjusted for baseline CFQ-R